For decades, cell replacement therapies have been assigned a bright future in all kinds of neurodegenerative diseases. Heterotopic transplantation of dopaminergic cells into the striatum has been performed for decades in various animal models for Parkinson’s disease (PD) as well as in a limited number of human studies, but cell survival and phenotype stability after transplantation particularly in stem cells studies have usually been limited, presumably due to local microenvironmental detriments. Additionally, this approach is associated with non-Werner, Storch & Fauser: Resuscitating the median forebrain bundle in Parkinson´s disease physiological afferent inputs to grafted cells within the heterotopic host brain region which accounts for limited functional integration into host brain circuitries. To overcome these limitations, we will advance the often neglected transplantation strategy of orthotopic grafting by utilizing engineered induced pluripotent stem cell (iPSC)-derived dopaminergic tissue for transplantation into the Substantia nigra of a Parkinsonian rat model to reconstruct the nigrostriatal dopaminergic pathway within its physiological circuitries.We plan to further advance the technique of “bridging” transplantation by grafting dopaminergic cells orthotopically into the site of pathology – the Substantia nigra pars compacta – combined with novel functionalized biomaterials to promote guided nigro-striatal axonal outgrowth to the striatum as the target area of dopaminergic neurons. We will use our starPEG-heparin hydrogel platform loaded with RGD (a tripeptide with an Arg-Gly-Asp sequence as an integrin binding domain), glial cell derived nerve growth factor (GDNF) and fibroblast growth factor-2 (FGF-2) as the bridging material between the Substantia nigra and the striatum. We already tested a variety of biofunctional artificial matrices for their potential of promoting dopaminergic maturation and especially axonal outgrowth of primary cells as well as stem cell preparations in vitro. From these studies, we have established an injectable biomaterial based on star-polyethylene glycole(PEG)-heparin hydrogel matrices functionalized with RGD peptide and dopaminergic growth factors, which promotes cell survival ,maturation and axonal sprouting of dopaminergic cells generated from various sources in vitro. Due to their superior dopaminergic differentiation capacity, transplants will be obtained directly from iPSC-derived neural progenitor cells (NPCs). After orthotopic transplantation of the engineered dopaminergic tissue, we will analyze behavioral and histological restitution of the Parkinsonian phenotype in the 6-hydroxydopamine rat PD model. Since we